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Abstract Background Decreased kidney function, indicated by a lower estimated glomerular filtration rate (eGFR), may affect interpretation of Alzheimer's disease (AD) blood biomarkers, including phosphorylated tau ( p ‐tau) and amyloid‐beta (Aβ) peptides, due to altered clearance. However, there is limited data available to determine the influence of eGFR on these biomarkers and whether it differs by biomarker or assay type, especially in racially diverse studies of community‐based older adults. Methods We used data from 557 participants in the Mayo Clinic Study of Aging (Rochester, MN n = 182; age 79±8 years; 36.3% Female, White participants) and the UMMC MIND Center‐Mayo Clinic Study of Aging (Jackson, MS n = 375; age 69±8 years; 73% Female 27% Black participants). eGFR was determined using the 2021 CKD‐EPI Creatinine equation. Plasma biomarkers were measured using the Lumipulse immunoassays for p ‐tau217, Aβ42, and Aβ40 (Fujirebio Diagnostics; n = 420); or the mass spectrometry‐based PrecivityAD2 assay (C2N Diagnostics; n = 253) for p ‐tau217, np‐tau217, Aβ42, and Aβ40. Common ratio values were calculated. Aβ42/40 measures were inverted so higher values are worse for all biomarkers. Log base‐2 transformed regression analysis related eGFR to each single analyte and ratio; coefficients (95% CI) reflect estimated doubling in biomarker per doubling in eGFR. Group specific [MN White ( n = 182), MS White ( n = 224), MS Black ( n = 151) participants] estimates are reported, as the distribution of social determinants of health can vary across populations and locations. Results Lower eGFR was associated with higher (worse) AD‐plasma biomarkers, and group stratified estimates were mostly consistent (Figure 1). Ratios of biomarkers diminished but did not entirely alleviate associations with eGFR. For example, MN White participants’ C2N p ‐tau217 association of ‐1.47 (‐1.94, ‐1.00), was attenuated to ‐0.67 (‐1.11, ‐0.22), when using p ‐tau217/np‐tau217. Conclusions Kidney function may be associated with AD‐plasma biomarker values, even with common ratio corrections. There was not strong evidence for highly differential associations of eGFR by race/site categories, though sample sizes are currently limited. The implications for diagnosis and risk classification need to be explored further to support health equity. Optimal consideration of comorbidities on blood biomarker concentrations must continue to be informed by investigation in large, racially and ethnically diverse, community‐based studies.

Abstract Background Plasma biomarkers show promise as a noninvasive method for measuring Alzheimer's disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late‐life brain morphology in community‐dwelling populations requires further investigation. Method Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received an adjudicated cognitive diagnosis and underwent 3 Tesla magnetic resonance imaging scans. Whole‐brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993‐95, mean age 59.0 years) and late‐life (2011‐13, mean age 76.8 years) from a subsample of 1,515 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid‐β (Aβ)42/40, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of plasma biomarkers from midlife, late‐life, and the change from midlife to late‐life with cortical thickness in late‐life. Interactions and effect modification by age were examined in exploratory analyses. Result The sample (Table 1) included 920 (60.7%) women, 387 (25.5%) Black participants, 513 (33.9%) participants with mild cognitive impairment, and 85 (5.6%) participants with dementia. The average age in late‐life was 76.8 (5.3 SD) years and the average cortical thickness was 2.27 (0.11 SD) millimeters. Cortical thickness was lower in individuals with adjudicated mild cognitive impairment or dementia compared to individuals without cognitive impairment (2.25 mm versus 2.29 mm, p <0.0001). In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p ‐Tau181 and increases from midlife to late‐life in NfL and GFAP were associated with lower cortical thickness in late‐life (Table 2). Concurrent measures of plasma biomarkers in late‐life were associated with lower cortical thickness (Table 2) and exhibited a stronger association among participants ≥75 years compared to <75 years (Table 3). Conclusion Plasma biomarkers of Alzheimer's disease pathology and neurodegeneration obtained in midlife and late‐life were associated with late‐life differences in cortical thickness. Additional longitudinal research is needed to determine whether plasma biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

Abstract Background The Overlap Index (OI) as previously published (Lee et al., 2022) is a reliable method for detecting tau accumulation using tau‐PET imaging (flortaucipir; AV1451). It identifies voxel‐wise standardized uptake value ratio (SUVr) elevations across serial scans. Although OI showed more sensitivity to tau signal elevation and longitudinal change than standard ROI measures, to our knowledge, the relationship of the tau PET overlap index to neuropathologic findings is still unclear. This study aims to investigate the potential of OI to detect NFTs of the neuropathologic Braak tangle stage, especially the early Braak tangle stage (I–IV). Method This study included 57 participants from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center, all of whom underwent autopsy and at least two serial AV1451 tau‐PET scans and 3T T1‐weighted MRI within an average of 16 months. Tau‐PET SUVr images were normalized to cerebellar crus grey matter, and MR images were co‐registered to a single‐subject MRI mean. Tau‐PET scans were resampled into MRI space, and OI was calculated by applying intensity thresholds 1.3. Clusters with fewer than 20 contiguous voxels were excluded. An OI cutoff of 0.5 was used and an SUVr cutoff of 1.29. Postmortem immunohistochemistry (IHC) using phospho‐tau antibodies (AT8, PHF‐1) was performed on the amygdala, temporal cortex (middle and superior), and anterior/posterior hippocampus. Neuropathological Braak staging was determined based on AT8‐stained sections. We conducted visual comparison of tau‐PET overlap signal in these regions with IHC‐confirmed tau pathology across Braak tangle stages. Result OI‐detected voxels corresponded to NFT distribution across Braak stages. In early Braak stages, standard SUVr‐based META‐ROI values remained negative, whereas OI showed positive signals, indicating greater sensitivity to early tau pathology (Figure 1). The spatial distribution of OI‐derived overlap regions aligned with high NFT burden, suggesting that OI captures early‐stage tau pathology more effectively than conventional SUVr methods. Conclusion OI in serial tau‐PET imaging demonstrated better detection of early‐stage tau pathology than standard ROI‐based SUVr measures. The alignment between OI‐detected voxels and neuropathological tau burden supports its potential as an in vivo biomarker for detecting early neurofibrillary tangles.

Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [ 18 F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [ 18 F]flortaucipir (ADNI), [ 18 F]MK‐6240 (CPAS), and [ 18 F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([ 18 F]flortaucipir) and AIBL ([ 18 F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [ 18 F]flortaucipir and [ 18 F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([ 18 F]PI‐2620) are underway.

Abstract Background T2*‐weighted imaging is of paramount importance for patient treatment eligibility and safety monitoring in anti‐amyloid pharmaceutical clinical trials and clinical care. Recently with the adoption of multi‐echo GRE (GRE) sequences, susceptibility weighted imaging (SWI), and quantitative susceptibility mapping (QSM) can be obtained in the same acquisition. In 2024, the QSM Consensus Organization Committee released a white paper recommending at least 1 mm isotropic voxel size for QSM. In clinical workflows microbleed detection is performed with higher in‐plane resolution (0.5x0.5mm 2 ), and large out‐of‐plane resolution (∼1.8mm), which was used in the ADNI4 protocol. In the CLARiTI protocol, a 1mm isotropic resolution was adopted. The objective of this work was to compare susceptibility estimates between the ADNI4 (0.5x0.5x1.8mm 3 ) and CLARiTI (1mm 3 ) protocols. Method The ADNI4 and CLARiTI QSM protocols were acquired on forty‐seven subjects (33 cognitively unimpaired (CU), 14 cognitively impaired (CI), in the same scan session. The groups were defined by their Clinical Demential Rating (CDR) global score (CDR global = 0 for CU, and CDR global >= 0.5 for CI subjects). QSM images were generated using publically available software (STI Suite, UC Berkeley). Mean susceptibility values in atlas regions were compared. Result Significant group differences (CU vs. CI) were observed in the fusiform and middle occipital gyrus with the ADNI4 protocol, only in the rectus with the CLARiTI protocol (Figure 1). These three regions are small in size and closer to surface‐air interfaces, which may have impacted estimation accuracy. However, in the substantia nigra and its sub‐regions (pars compacta and pars reticulata), which shows increased susceptibility in Lewy body disease, the ADNI4 and CLARiTI protocols were in good agreement (r 2 > 0.9) (Figure 2). Conclusion Group differences were observed between the ADNI4 and CLARiTI QSM only in 3 small regions close to surface‐air interfaces in this small dataset. The two techniques showed highly correlated (r 2 = 0.93) estimates in the substantia nigra, a region with high susceptibility due to iron deposition. Strong correlations between the two protocols are encouraging. Radiologists have historically preferred submillimeter in‐plane resolution for microbleed detection, which is more time manageable with anisotropic imaging.

Abstract Blood-based biomarkers show promise as a noninvasive method for measuring Alzheimer’s disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late-life brain morphology in community-dwelling populations requires further investigation. Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received underwent 3 Tesla magnetic resonance imaging scans. Whole-brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993-95, mean age 59.0 years) and late-life (2011-13, mean age 76.8 years) from a subsample of 1,515 participants (60.7% female, 25.5% Black adults) were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid-β (Aβ)42/40, phosphorylated tau at threonine 181 (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of blood-based biomarkers from midlife, late-life, and the change from midlife to late-life with cortical thickness in late-life. In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p-Tau181 and increases from midlife to late-life in NfL and GFAP were associated with lower cortical thickness in late-life. Concurrent measures of p-Tau181, NfL, and GFAP were associated with lower cortical thickness in late-life and exhibited a stronger association among participants ≥75 years old compared to participants &lt;75 years old. Additional longitudinal research is needed to determine whether blood-based biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.

Abstract Background Amyloid‐Related Imaging Abnormalities (ARIA), an adverse event associated with Alzheimer's disease anti‐amyloid immunotherapies, occur in the form of edema or sulcal effusion (ARIA‐E) and microhemorrhages and superficial siderosis (ARIA‐H). Conventional teaching is that ARIA‐H is permanent hemosiderin staining of the brain. In clinical trials we have noticed that some ARIA‐H microhemorrhages that occur with regional ARIA‐E appear to later resolve. The goal of this study is to illustrate that, opposed to current understanding, some ARIA‐H microhemorrhages may resolve. Methods We identified participants from the Dominantly Inherited Alzheimer's Network Trial Unit (DIAN‐TU) and open label extension (OLE) gantenerumab studies that had ARIA‐E and at least one ARIA‐H microhemorrhage. The T2* GRE sequence from all available MRI exams in a patient were co‐registered and reviewed by a board‐certified neuroradiologist. Individual microhemorrhages were tracked over the serial exams. We defined disappearing/resolving microhemorrhages as those appeared with or following ARIA‐E, were visualized on at least 2 MRI exams, and were subsequently not visualized on at least 2 MRI exams. Results A total of 12 patients met inclusion criteria of which 5 (41%) had microhemorrhages that resolved over 10‐40 months follow‐up after the incident ARIA. These microhemorrhages occurred in clusters in the region of ARIA‐E, and only some of the regional microhemorrhages resolved over follow‐up. Examples are shown in Figures 1‐3. Conclusions The disappearance (resolution) of ARIA‐H microhemorrhages is relevant to the management and continued dosing of patients receiving anti‐amyloid immunotherapies as this is guided by the presence of ARIA (including cumulative treatment emergent microhemorrhages) as well as clinical symptoms. A microhemorrhage number alone may not be indicative of the potentially dynamic nature of ARIA‐H.

Abstract Background White matter hyperintensity topography, particularly posterior confluent and subcortical multispot (WMH‐MS), has been implicated as surrogate imaging biomarker of cerebral amyloid angiopathy (CAA). Usefulness of WMH‐MS for prediction of future cerebral microbleeds (CMB's) has significant clinical implications for anti‐amyloid therapy risk assessment. Our primary goal was to identify the prevalence of positive WMH‐MS status and their utility for predicting the incident CMBs in a population‐based sample. Our secondary goal was to evaluate its usefulness after accounting for amyloid (surrogate for CAA) and WMH burden (surrogate of small vessel disease) which are both risk factors for CMBs. Method We identified 651 participants (mean age (SD) 69.8 (10.0) years, 55% male) from the Mayo Clinic Study of Aging, who had 3T baseline whole brain fluid‐attenuated inversion recovery (FLAIR) MRI and at least two T2*‐weighted gradient recalled echo (GRE) sequences (concomitant with or after FLAIR) which were used to ascertain CMBs. Amyloid positron emission tomography (PiB‐PET) scans were available in 87% of the sample. Visual reads on FLAIR scans were performed using a 4‐point Fazekas rating scale of periventricular and deep WMH (positivity: Fazekas ≥ 2) and a 3‐point MS severity visual scale (positivity: nWMH‐MS > 10 circular or ovoid WMH spots, Figure 1) according to established criteria. Using univariate and multivariable logistic regression, we assessed the independent association of WMH‐MS > 10 and Fazekas ≥ 2 for prediction of incident CMB's. Result The frequency of WMH‐MS pattern was greater in those who developed an incident CMB compared to those who did not develop a CMB (20.8% vs. 2.8%, p < 0.001). Older age and male sex were predictive of incident CMBs (Figure 2A). In univariate models, presence of WMH‐MS pattern but not Fazekas was associated with incident CMBs after adjusting for age and sex. The associations remained significant after additional adjustment for APOE4 , hypertension, number of baseline CMBs (Prior CMB), and amyloid effects (Figure 2B). Conclusion Visually identified WMH‐MS patterns on FLAIR‐MRI were predictive of incident CMBs in this population and may be useful markers of CAA. Future studies evaluating its utility as an additional biomarker of amyloid related imaging abnormalities in clinical trials are necessary.

Abstract Background Cognitive resilience to Alzheimer's disease (AD) pathology has been widely studied, but distinguishing resilient individuals from those with typical tau pathologies remains challenging due to the overlap in imaging and plasma biomarker profiles. We hypothesize that our machine learning‐based (ML) tau heterogeneity score, THETA (JNUMED, July 2024), could serve as an effective marker of resilience and provide a better estimation of tau's temporal progression. Method Longitudinal imaging data from the Mayo Clinic Study of Aging (MCSA, n = 1834) and ADRC ( n = 246) were analyzed. Participants were categorized into typical AD and resilient groups using amyloid PiB‐PET (abnormal PiB‐PET≥25 Centiloid units), Flortaucipir (FTP‐PET) (meta‐ROI≥1.29 SUVr, ERC≥1.27 SUVr) and Mini‐Mental State Examination (MMSE). Typical AD was defined as abnormal PiB‐PET and abnormal FTP‐PET for both biomarkers (Figure 1). Resilience to AD pathology was determined by predicted values of MMSE >28 from a linear mixed effects model for cognitively unimpaired participants. In addition, a resistant group was broadly defined as having normal PiB‐PET. To capture the spatial heterogeneity of tau distribution in the brain, regional THETA scores were generated using ML model and visual ratings. Additionally, a progression model, Sampled Iterative Local Approximation (SILA), was fitted using AD and plasma biomarkers ( p ‐tau181 and GFAP) for validation. Result THETA identified regions of reduced tau uptake in the frontal, parietal, temporal, occipital, and limbic regions when compared to the typical AD group (Figure 2A). This was confirmed by the preserved cortical thickness in these same regions (Figure 2D). In addition, SILA showed THETA can distinguish global tau temporal progressions of typical AD, resilient, and resistant groups compared to the other biomarkers (Figure 3). Interestingly, the onset age for GFAP was younger for resilient and typical AD, indicating earlier onset of inflammation in the presence of pathology. Conclusion The significant regions identified by THETA, showing reduced tau and preserved cortical thickness, combined with the clear offset in progression models between resilient and typical AD, suggest that THETA may help uncover pathological tau mechanisms that differentiate these groups. These findings highlight the potential of THETA to provide valuable insights into resilience mechanisms and enhance our understanding of AD.